WASp modulates RPA function on single-stranded DNA in response to replication stress and DNA damage

Seong-Su Han; Kuo-Kuang Wen; María L García-Rubio; Marc S Wold; Andrés Aguilera; Wojciech Niedzwiedz; Yatin M Vyas

doi:10.1038/s41467-022-31415-z

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WASp modulates RPA function on single-stranded DNA in response to replication stress and DNA damage

Journal article

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WASp modulates RPA function on single-stranded DNA in response to replication stress and DNA damage

Seong-Su Han, Kuo-Kuang Wen, María L García-Rubio, Marc S Wold, Andrés Aguilera, Wojciech Niedzwiedz and Yatin M Vyas

Nature communications, Vol.13(1), pp.3743-3743

06/29/2022

DOI: 10.1038/s41467-022-31415-z

PMCID: PMC9243104

PMID: 35768435

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Abstract

Perturbation in the replication-stress response (RSR) and DNA-damage response (DDR) causes genomic instability. Genomic instability occurs in Wiskott-Aldrich syndrome (WAS), a primary immunodeficiency disorder, yet the mechanism remains largely uncharacterized. Replication protein A (RPA), a single-strand DNA (ssDNA) binding protein, has key roles in the RSR and DDR. Here we show that human WAS-protein (WASp) modulates RPA functions at perturbed replication forks (RFs). Following genotoxic insult, WASp accumulates at RFs, associates with RPA, and promotes RPA:ssDNA complexation. WASp deficiency in human lymphocytes destabilizes RPA:ssDNA-complexes, impairs accumulation of RPA, ATR, ETAA1, and TOPBP1 at genotoxin-perturbed RFs, decreases CHK1 activation, and provokes global RF dysfunction. las17 (yeast WAS-homolog)-deficient S. cerevisiae also show decreased ScRPA accumulation at perturbed RFs, impaired DNA recombination, and increased frequency of DNA double-strand break (DSB)-induced single-strand annealing (SSA). Consequently, WASp (or Las17)-deficient cells show increased frequency of DSBs upon genotoxic insult. Our study reveals an evolutionarily conserved, essential role of WASp in the DNA stress-resolution pathway, such that WASp deficiency provokes RPA dysfunction-coupled genomic instability.

Details

Title: Subtitle: WASp modulates RPA function on single-stranded DNA in response to replication stress and DNA damage
Creators: Seong-Su Han - University of Iowa
Kuo-Kuang Wen - University of Iowa
María L García-Rubio - Universidad Pablo de Olavide
Marc S Wold - Roy J. and Lucille A. Carver College of Medicine
Andrés Aguilera - Universidad Pablo de Olavide
Wojciech Niedzwiedz - Institute of Cancer Research
Yatin M Vyas - University of Iowa
Resource Type: Journal article
Publication Details: Nature communications, Vol.13(1), pp.3743-3743
DOI: 10.1038/s41467-022-31415-z
PMID: 35768435
PMCID: PMC9243104
NLM abbreviation: Nat Commun
eISSN: 2041-1723
Grant note: DOI: 10.13039/100000060, name: U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases, award: R01AI146380; DOI: 10.13039/501100000650, name: Institute of Cancer Research, Royal Cancer Hospital, award: A24881
Language: English
Date published: 06/29/2022
Academic Unit: Stead Family Department of Pediatrics; Radiation Oncology; Biochemistry and Molecular Biology
Record Identifier: 9984288731502771

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